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Abstract Autoimmunity is often observed among individuals with primary immune deficiencies; however, the frequency and role of autoimmunity in Schimke immuno-osseous dysplasia (SIOD) has not been fully assessed. SIOD, which is caused by mutations of SMARCAL1, is a rare autosomal recessive disease with its prominent features being skeletal dysplasia, T cell deficiency, and renal failure. We present a child with severe SIOD who developed rituximab resistant Evans syndrome (ES). Consistent with observations in several other immunodeficiency disorders, a review of SIOD patients showed that approximately a fifth of SIOD patients have some features of autoimmune disease. To our best knowledge this case represents the first patient with SIOD and rituximab resistant ES and the first study of autoimmune disease in SIOD.

Purpose: The primary objective of this study was to compare clinical outcomes of very low birth weight (VLBW) infants with 25-hydroxy vitamin D [25(OH)D] levels <25 nmol/l in umbilical cord blood versus VLBW infants with 25(OH)D levels in cord blood >25 nmol/l. The secondary objective was to evaluate umbilical cord vitamin D as a risk factor for respiratory distress syndrome (RDS) in preterm infants., Methods: We examined 25(OH)D levels in umbilical cord blood and in infants' serum at discharge from the neonatal intensive care unit. We evaluated the associations between severe vitamin D deficiency and various laboratory findings and clinical outcomes., Results: Eighty one infants with birth weight less than 1500 g met the entry criteria for this study and were divided to groups according to umbilical cord blood vitamin D [Group A: 25(OH) D  < 25 nmol/l; 10 ng/ml and Group B: 25(OH) D  > 25 nmol/l; 10 ng/ml]. Overall, 81.5% of the infants had a 25(OH)D level <50 nmol/L and 44.4% had a level <25 nmol/L. The laboratory findings and the subsequent clinical outcomes were comparable in infants in both groups (non-significant difference). Only the infants in the 25(OH) D  25 nmol/L group had a lower calcium in urine at age 28 d ( p =.0272). In addition, we found in this study that umbilical cord vitamin D level does not lead to a higher or lower risk of RDS (odds ratio 1.044; 95% confidence interval 0.349-0.88; p =.0771)., Conclusions: In our prospective cohort study, we found no significant association between vitamin D status and selected clinical outcomes when using a cut-off of 25 nmol/l (severe vitamin D deficiency) in preterm infants.

Purpose: To evaluate vitamin D status in mothers and their very low birth weight infants (VLBW) at birth (umbilical cord blood) and at discharge with currently recommended supplementation of vitamin D. Methods: Ninety-four infants with birth weight less than 1500 g completed the study. The total daily vitamin D intake was 800-1000 IU. We examined 25-hydroxyvitamin-D [25(OH)D] levels in maternal serum before labor, in cord blood, and in infants' serum at discharge. Results: Median (IQR) serum 25(OH)D was 21 (14-36) nmol/l [8 (6-15) ng/ml] in cord blood, and 46 (37-60) nmol/l [18 (15-24) ng/ml] at discharge. Serum 25(OH)D was <50 nmol/L in 71.3% of mothers, in 91.5% of cord blood samples, and in almost 60% of preterm newborns at discharge (after 8 weeks of supplementation). Serum 25(OH)D was <75 nmol/L in 88.3% of mothers, in 97.9% of cord blood samples, and in 91.4% of preterm newborns at discharge. Conclusions: In our cohort, we found that due to the very high prevalence of 25(OH)D deficiency among mothers, the current generally recommended dose of vitamin D (800-1000 IU per day) for VLBW infants was unable to improve vitamin D levels above the desired 50 or even 75 nmol/L before discharge.

Purpose: The aim of this pilot study was to estimate physiological parathyroid hormone (PTH) levels and their relationship with bone metabolism parameters in otherwise healthy preterm newborns with birth weight 1000-1500 g. Methods: PTH, 25(OH)D, S-Ca, S-P, and ALP were analysed from blood samples obtained from 20 preterm infants once a week up to the 36th gestational week. Results: Of the total 134 examined serum samples for PTH levels, the estimated range was 1.6-9.3 pmol/l (15.1-87.7 pg/ml). No statistically significant correlation of PTH level with that of S-Ca, S-P, or ALP was observed, except for the 56th day of life ( p  = .03; Rho = 0.76; n  = 8). From the second month of life, there was a statistically significant relationship only between PTH and 25(OH)D (Rho = -0.71, p ≤ .0001). In our cohort, vitamin D deficiency (20 ng/ml) occurred in 75% at birth and at 30% in the 36th gestational week. Conclusions: The physiological range indicated by the measurements was close to the reference limits for adults (1-7 pmol/l; 9.4-66 pg/ml). PTH level above this range can be considered as hyperparathyroidism in preterm neonates.

Hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma (HLRCC)/fumarate hydratase deficient renal cell carcinoma (FHRCC) is defined by molecular genetic changes (mutation/LOH in fumarate hydratase (FH) gene). We investigated chromosomal numerical aberration pattern (CNV) in FHRCC/HLRCC using array comparative genomic hybridization analysis and low pass whole genome sequencing. Genetic analysis was successfully completed in 12 tumors. Most common chromosomal aberrations detected were a complete or partial loss of chromosome 4 (5/12 cases), chromosome 15 (4/12 cases), and chromosomes 9, 13, and 14 (each in 3/12 cases), as well as a complete or partial gain of chromosome 17 (in 4/12 cases). No chromosomal losses or gains were detected in 4 cases. Copy number variation pattern in FHRCC/HLRCC appears to be highly variable and does not provide a useful diagnostic tool in identifying these cases. Immunohistochemical staining and especially molecular genetic evaluation of FH gene mutations/LOH remain the gold standard in identifying FHRCC/HLRCC., (Copyright © 2019. Published by Elsevier Inc.)

Transient hyperphosphatasemia of infancy and early childhood (THI) is characterized by transiently increased activity of serum alkaline phosphatase (S-ALP), predominantly its bone or liver isoform, in children under five years of age. There are no signs of metabolic bone disease or hepatopathy corresponding with the increased S-ALP. THI is benign disorder, rather laboratory than clinical disorder, which is usually accidentally detected in both healthy and sick children. When encountered in a child with either chronic bone, liver or kidney disease, it might concern the physician. We present a three year old boy with genetically confirmed Gitelman syndrome where THI was detected accidentally during periodic check-up. S-ALP peaked to 41.8 µkat/L, there were neither laboratory or clinical signs of liver or bone disease; the S-ALP dropped to normal value of 4 µkat/L 60 days later. Therefore, the patient fulfilled the criteria for THI. There were no further increases in S-ALP.

Stem cells are unique pools of cells that are crucial for embryonic development and maintenance of adult tissue homeostasis. The landmark Nobel Prize winning research by Yamanaka and colleagues to induce pluripotency in somatic cells has reshaped the field of stem cell research. The complications related to the usage of pluripotent embryonic stem cells (ESCs) in human medicine, particularly ESC isolation and histoincompatibility were bypassed with induced pluripotent stem cell (iPSC) technology. The human iPSCs can be used for studying embryogenesis, disease modeling, drug testing and regenerative medicine. iPSCs can be diverted to different cell lineages using small molecules and growth factors. In this review we have focused on iPSC differentiation towards cardiac and neuronal lineages. Moreover, we deal with the use of iPSCs in regenerative medicine and modeling diseases like myocardial infarction, Timothy syndrome, dilated cardiomyopathy, Parkinson's, Alzheimer's and Huntington's disease. Despite the promising potential of iPSCs, genome contamination and low efficacy of cell reprogramming remain significant challenges.

Introduction: Association between high serum homocysteine (S-Hcy) levels and low bone mineral density (BMD) and increased fracture risk in postmenopausal women has been documented. Data concerning S-Hcy and bone health in children are scarce., Objective: Our aim was to evaluate S-Hcy in children and adolescents with impaired bone health and look for correlations with clinical and laboratory data., Patients and Methods: We assessed S-Hcy levels in 37 children and adolescents (22 boys and 15 girls; mean age 13.9 ± 3.5 years) with prevalent low-energy trauma fractures (mean 3.3 ± 2.3 per patient) and/or low spinal L1-L4 BMD (below -2SD Z-score; DXA Lunar GE). We also evaluated S-ALP, serum CrossLaps, osteocalcin (S-OC), body height, weight, body mass index (BMI) and serum levels of folate and vitamin B12. At the time of assessment, the children were not taking any drugs known to influence bone metabolism. The age-dependent parameters were expressed as Z-scores ± SD., Results: S-Hcy Z-score was significantly higher (1.3 ± 1.5; P < 0.0001) and L1-L4 BMD Z-score was significantly lower (-1.7 ± 1.3; P < 0.0001), respectively, in comparison with reference values. S-ALP did not differ from reference values (P = 0.88), while S-CrossLaps and S-osteocalcin were higher (1.2 ± 1.8 and 0.4 ± 0.5; P = 0.0001 and P = 0.001, respectively). S-Hcy was inversely correlated to L1-L4 BMD (r = -0.33; P = 0.05) and S-ALP (r = -0.36; P = 0.04) and not related to number of prevalent fractures (r = 0.01), S-osteocalcin (r = -0.22) or S-CrossLaps (r = 0.003)., Conclusion: These results suggest increased bone turnover and negative influence of elevated S-Hcy on bone formation and BMD in children and adolescents with recurrent fractures.

Idiopathic infantile hypercalcemia (IIH) is a rare disorder caused by CYP24A1 loss-of-function mutation, resulting in impaired degradation of 1,25-dihydroxyvitamin D3. Pamidronate, an intravenously administered bisphosphonate, which is a potent inhibitor of bone resorption, has been reported only once for treatment IIH. We present a case of a previously healthy 5-month-old boy with IIH, where calcemia peaked to 5 mmol/L. Treatment with methylprednisone and furosemide had only minor effects; therefore, 2 intravenous infusions of pamidronate (0.6 mg/kg per dose) corrected the serum calcium level to 2.95 mmol/L. Furthermore, CYP24A1 homozygous mutation p.R396W (c.1186c&gt;t) was identified in this patient, confirming the clinical diagnosis of IIH. In conclusion, IIH has a favorable outcome once properly detected and appropriately treated. Pamidronate has a beneficial effect in those patients with IIH where glucocorticoids and furosemide fail to meet the expectations. &nbsp;

Introduction: Gitelman syndrome (GS) is a very rare autosomal recessive tubulopathy due to loss-of-function or mutation in solute carrier family12, member 3 gene (SLC12A3 gene) encoding thiazide-sensitive NaCl co-transporter in the distal convoluted tubule, leading to hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria and low-to-normal blood pressure. Clinical signs are mostly secondary to chronic hypokalemia and include dizziness, fatigue, constipation and weakness. Patients can also present with muscle cramps, tetany, fatigue and convulsions due to severe metabolic alkalosis or hypomagnesemia. Manifestations of GS are rarely apparent before the age of five, and the syndrome is usually diagnosed during adolescence or adulthood. Here we describe a case of GS presenting in infancy with hypokalemia and psychomotor retardation., Case Report: We present an 18-month-old boy who presented with psychomotor retardation and failure to thrive. Investigations revealed hypokalemia at 2.7 mmol/L, metabolic alkalosis, hypocalciuria and normal serum magnesium level. The diagnoses of Barter syndrome (BS) and Gitelman syndrome (GS) were considered. Genetic studies confirmed the diagnosis of GS and three different mutations of in SLC12A3 gene were detected. Two mutations (c.2576T>C and c.2929C>Ty) were considered as causal ones, with the patient´s parents being the heterozygous carriers. Oral potassium supplementation resulted in normalisation of the hypokalemia and psychomotor improvement., Conclusion: We report a rare case of psychomotor retardation occurring at an early age in genetically confirmed GS. In spite of being a rare disorder, GS has to be considered in children with developmental delay and muscle weakness. With adequate treatment, GS patients have an excellent prognosis.

Introduction: Renal biopsy (RB) is a decisive diagnostic procedure for patients with renal disease. Our aim was to assess the safety of RB and the prevalence of associated clinical complications., Methods: A total of 166 RBs were performed in 164 children (88 boys, 76 girls) in East Bohemia in 1997-2007. The mean age of the children was 12.9 +/- 4.1 years. All RBs were performed by a single consultant nephrologist. 27 biopsies were performed in 27 patients (16.3 percent) in 1997 under radiography control, while the remaining 139 biopsies (83.7 percent) were performed under ultrasonographic guidance. Renal ultrasonography (USG) following RB was not a general rule in patients who were biopsied under radiography control before 1998; therefore, only the USG results in patients after USG-guided RB (n = 139) were evaluated., Results: No major complications were encountered, and only minor complications occurred in 39 (23.5 percent) patients, which did not require medical intervention. The most common complication was asymptomatic perirenal haematoma, which was detected by USG one to three days after a USG-guided RB (30 out of 139 biopsies; 21.6 percent). Perirenal haematoma accompanied by abdominal pain occurred in two (1.4 percent) patients. Macroscopic haematuria was present in seven (4.2 percent) patients on Days 1-3 post biopsy. The complications were neither age-dependent nor were they related to the serum creatinine levels., Conclusion: The results obtained are consistent with those in other reports of paediatric patients. The absence of major complications is a favourable outcome. Thus, the present practice of USG-guided percutaneous RB in children is safe and clinically beneficial.

Background: There is lack of consensus on the necessity of renal biopsy in children with steroid-dependent nephrotic syndrome (SDNS) prior to cytotoxic therapy., Objectives: To retrospectively evaluate: (a) the benefit of renal biopsy (RB) prior to cyclophosphamide therapy; (b) relationship between histopathologic results of RB samples and clinical course in children with SDNS., Patients, Materials and Methods: RB was performed in 18 SDNS patients (11 boys and 7 girls). The mean age of the children at the time of nephrotic syndrome (NS) diagnosis was 6.4 +/- 3.9 years and 9.7 +/- 4.3 years at the time of RB. Following the RB, all children received prednisone and cyclophosphamide treatment for 12 weeks. Duration of remission and relapse rate was recorded., Results: The histologic evaluation revealed minimal change disease (MCD; n = 14) and IgM nephropathy (n = 4). These results didn't affect the ongoing therapy. MCD patients had longer remission compared to IgM nephropathy (3.2 +/- 1.5 vs 1.7 +/- 0.8 years; p = 0.05). Relapse rate did not differ significantly between MCD and IgM nephropathy (p = 0.22). The duration of remission was inversely correlated to relapse rate after the treatment (r = -0.66, p = 0.01)., Conclusion: We suggest that RB prior to cyclophosphamide therapy is not necessary in patients with SDNS (Tab. 2, Ref. 14). Full Text (Free, PDF) www.bmj.sk.

Objectives: The aim of this study was to measure U-NAG in children with vesicoureteral reflux (VUR) and examine the relationship between selected clinical parameters., Background: U-NAG/creatinine ratio is a marker of renal tubular impairment and an increase in this ratio have been reported to affect the kidneys in various diseases., Methods: The U-NAG/creatinine ratio was measured in the spot urine of 22 children (10 boys and 12 girls, mean age 2.83 +/- 2.42 years) with VUR. In 8 patients The VUR was unilateral grade I-IV (8 patients), and it was was bilateral, grade I-V in 14 patients. In patients with bilateral reflux and different VUR grade on each side, the highest grade of VUR was taken into consideration., Results: The U-NAG/Cr levels were significantly higher in VUR patients compared to the reference (p = 0.0001). There was no difference in U-NAG/Cr between children with unilateral (n = 8) and bilateral (n = 14) VUR (p = 0.66). There was no difference in U-NAG/Cr between patients with VUR grades I-III and IV-V (p = 0.67). The U-NAG/Cr activity was higher in patients with reflux nephropathy (RN; n = 9) when compared to reference data (p = 0.0001), however there was no difference in comparison to children without RN (p = 0.84)., Conclusions: U-NAG/Cr increased in children with VUR grade I-V and there is a very weak relationship with the grade of VUR. U-NAG/Cr is a useful marker of renal tubular impairment, however there is poor relationship with the degree of kidney damage in patients with VUR (Tab. 1, Ref. 25). Full Text (Free, PDF) www.bmj.sk.

5-aminosalicylate compounds (mesalazine, sulfasalazine) are widely used in therapy of inflammatory bowel diseases. Mesalazine-induced interstitial nephritis is a rare complication; however, the morbidity in an affected individual is high. Regular renal screening in patients treated with 5-aminosalicylate compounds is important. A 15-year-old boy with treated idiopathic proctocolitis, consequent mesalazine-induced nephritis, and a favorable response to corticotherapy is presented.

A 16-year old girl presented with rapid onset of muscular weakness and a history of severe dysphagia, dysphonia and significant wasting. On examination, she was dystrophic (BMI 15.7) and had signs of myopathy. Laboratory findings confirmed myopathy (CPK 106.4 microkat/L (6384 IU/L), AST 2.86 microkat/L (171.6 IU/L), myoglobin 1582 microg/L). There was profound hypokalaemia (S-K 1.8 mmol/L) suggesting hypokalaemic paralysis. Diagnosis of distal renal tubular acidosis (dRTA) was based on combination of hyperchloremic metabolic acidosis, severe hypokalaemia, high urinary pH and positive value of urinary anion gap. There was evidence of other signs of renal tubular impairment (urinary beta-2-microglobulin 213 mg/L, glomerulotubular proteinuria 1.01g/24h). Autoimmune tests (rheumatoid factor, antinuclear antibodies, autoantibodies to Ro/SSA and La/SSB) together with symptoms of xerostomia with swallowing difficulties and atrophic glossitis suggested primary Sjogren's syndrome (SS) as the underlying cause of dRTA. The renal biopsy confirmed chronic tubulo-interstitial nephritis compatible with this diagnosis. Full recovery of muscle weakness and hypokalaemia and acidosis followed after potassium and alkali replacement therapy. Corticosteroids were administered with subsequent addition of cyclosporine A because of disease activity. In conclusion, primary SS is a rare diagnosis in childhood and adolescence and should be considered in patients presenting with hypokalaemic paralysis, as this might be due to dRTA, even in the absence of apparent sicca syndrome.

Background: An intracardiac thrombus is extremely rare in children with the nephrotic syndrome (NS)., Objectives: To present a case report of a child with steroid resistant NS and intracardiac thrombus., Methods and Results: A 3.5-year-old boy with the first attack of steroid resistant NS was admitted to the hospital. A histological evaluation of the renal biopsy specimen revealed the minimal changes disease (MCD). There were no mutations in the podocin gene. The treatment with furosemide, albumin, prednisone, metylprednisolone, cyclophosphamide, enalapril and losartan was ineffective, as the intermittent oedema, proteinuria, hypoalbuminemia and hypercholesterolemia were still present. 8 weeks after the disease onset, the sinus tachycardia occurred and the echocardiography revealed a thrombus in the right ventricle, which had gradually proceeded to the pulmonary artery bifurcation. The thrombolysis with 40 mg of alteplase was initiated. Two hours after the alteplase application, the thrombus was not detectable. The mutational analysis of factors V, II and MFTHR genes were negative. The repeated echocardiography performed after 1 week, 2 and 6 months, respectively, revealed a normal cardiac function and morphology. The patient received prophylactic doses of fraxiparin for 3.5 months followed by warfarin. A remission of the nephrotic syndrome was achieved with high doses of cyclosporine A together with atorvastatin at 7 month after the disease onset., Conclusion: The thromboembolism as a result of the hypercoagulation status is a serious complication of the nephrotic syndrome. The intracardiac localisation of thrombus is extremely rare (Fig. 2, Ref. 10). Full Text (Free, PDF) www.bmj.sk.

Objective: Hydronephrosis leads to deterioration of renal function. As urinary N-acetyl-beta-D-glucosaminidase (U-NAG) activity is considered a sensitive marker of renal tubular impairment, our aim was to measure U-NAG in children with hydronephrosis and to look for a relationship among selected clinical parameters., Materials and Methods: We studied 31 children (22 boys and 9 girls, mean age 2.3 +/- 2.5 years) with hydronephrosis grade 1-4 that had U-NAG/creatinine ratio (U-NAG/Cr) measured., Results: The U-NAG/Cr was significantly higher in patients with hydronephrosis compared to reference data (p = 0.002). There was no difference in U-NAG/Cr between children with unilateral and bilateral hydronephrosis (p = 0.51). There was no significant difference in U-NAG/Cr between children with grades 1-3 (pooled data) and grade 4, respectively (p = 0.89). There was no correlation between U-NAG/Cr and the grade of hydronephrosis (r = 0.01)., Conclusions: U-NAG/Cr is increased in children with hydronephrosis grade 1-4, and there is no relationship with the grade of hydronephrosis. U-NAG is a useful marker of renal tubular dysfunction, however its relationship with the degree of kidney damage in patients with hydronephrosis should be considered as doubtful.

Background: Idiopathic hypercalciuria (IH) is defined as hypercalciuria that persists after correction of dietary inbalances and has no detectable causes. Patients with IH have a higher prevalence of osteoporosis. Defective reabsorption of calcium by the renal tubule is considered a likely mechanism of IH. N-acetyl-beta-D-glucosaminidase (NAG) is a lysosomal enzyme that is a very sensitive marker of renal tubular impairment., Methods: Fifteen patients (nine boys and six girls, mean age 12.4 +/- 4.0 years) with IH (urinary calcium excretion >0.1 mmol/kg per 24 h) had their bodyweight, height, body mass index (BMI), urinary NAG/creatinine ratio (U-NAG/Cr) and 24-h urinary calcium excretion (U-Ca/24 h) assessed. L1-L4 bone mineral density (BMD) was measured by dual energy X-ray absorptiometry and volumetric BMD (BMDvol) was calculated. The obtained results were expressed as Z-scores., Results: The values of basic anthropometric parameters did not differ significantly from the values of the reference population and there was a tendency to short stature, which did not reach statistical significance (P = 0.08). The values of calciuria and U-NAG/Cr were significantly higher while BMD was significantly lower when compared to the reference values (P < 0.0006, P < 0.006 and P < 0.001, respectively). Inverse and significant correlations were found between U-Ca/24 h and BMD, U-Ca/24 h and body height, and U-Ca/24 h and BMDvol (r = -0.64 and -0.70, respectively, P < 0.01; r = -0.55, P < 0.05), while there was no correlation between U-NAG/Cr and U-Ca/24 h, nor between BMD and weight or BMD and BMI., Conclusion: Tubular impairment is highly probable in children with IH, but there is a poor relationship with the degree of calcium leakage. Idiopathic hypercalciuria should be considered as a risk factor for stunted growth and low bone mass.

Aim: The principal aim was to establish paediatric reference data for the urinary N-acetyl-beta-D-glucosaminidase (U-NAG) activity., Method and Results: Two hundred and sixty-two healthy children aged 0-18 years (0-1 month, n = 38; 1 month-1 year, n = 50; 1-3 years, n = 50; 3-6 years, n = 46; 6-10 years, n = 29; 10-18 years, n = 49) had a urine sample collected and the U-NAG activity was evaluated by using fluorimetry and related to urinary creatinine as a nkat/mmol ratio. A strong age dependence of the U-NAG/creatinine ratio and its high interindividual variability in children was observed; the highest values of upper reference range being in the 0-1 month and 1 month-1 year groups (134.8 and 50, respectively), which dropped gradually to 7.25 in the oldest age group (10-18 years)., Conclusion: The establishment of urinary NAG reference paediatric values is a potentially useful tool for the proper evaluation of renal tubular impairment in children.